Fentanyl is a synthetic opioid analgesic used to treat moderate to severe chronic pain. Fentanyl, whose chemical name is N-Phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide, has the following chemical formula:
Fentanyl and its congeners, sufentanil, alfenanil, and remifentanil, all act as opioid agonists mainly on mu-receptors that are present along the central nervous system. Mu-binding sites are present in the human brain, spinal cord, and other tissues that are integral to the transmission of pain pathways. Therapeutic use of intravenous fentanyl results in a rapid onset but a short duration of action, making this route of administration a popular choice as an anesthetic adjuvant. Fentanyl's low molecular weight, high potency, and lipid solubility also makes it suitable for transdermal delivery. The development of transdermal fentanyl, a less invasive route of administration compared to intravenous delivery, has facilitated the use of fentanyl to manage chronic pain. Transdermal fentanyl patches, such as the DURAGESIC® fentanyl transdermal system sold by Janssen Pharmaceuticals, adhere to skin and provide a prolonged, continuous, slow, and therapeutic dose of fentanyl for up to 72 hours.
As with all potent mu opioid analgesics, fentanyl also is abused for its intense euphoric effects. Abusers seek rapid drug absorption. To get high, abusers often cut a small piece of the fentanyl patch and swallow it or suck on it. These actions provide abusers with a rapidly absorbed, high blood level of fentanyl, resulting in euphoric effects. Non-medicinal use of transdermal fentanyl patches is extremely dangerous and can result in opioid addiction, overdose, or death. Even after a 72 hour transdermal usage interval, some residual fentanyl remains in the patch. Unused or used fentanyl patches are therefore also susceptible to unintentional misuse, such as accidental exposure to a transdermal fentanyl patch by children or family pets.
Methods or paradigms of abusing fentanyl transdermal patches include, for example, single or multistep extraction, physical tampering with subsequent extraction and direct administration by oral routes such as chewing or swallowing, inhalation abuse (e.g., smoking) by heating or burning, or trans mucousal absorption across tissues in the oral cavity or across membranes in the rectal cavity. Documented methods of abusing fentanyl patches include injecting fentanyl extracted from a patch intravenously, chewing or swallowing patches, inserting patches into the rectum, inhaling fentanyl volatilized from the adhesive or gel, and extracting fentanyl in tea. The biological effects of fentanyl are similar to those of street heroin but fentanyl is approximately one hundred times more potent. It is extremely difficult to stop its absorption because fentanyl is highly lipophilic and penetrates the central nervous system easily. Therefore, the illicit use of fentanyl is very dangerous and causes numerous opioid overdose deaths. See, W. Guan, et al., Prim Care Companion CNS Disord. 2011, 13(5); http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267509/ (accessed Aug. 10, 2014).
Curtailing the misuse and abuse of fentanyl and other opioid analgesics is a difficult problem. Several approaches have been tried: formulation technologies aimed at introduction of functional characteristics that deter or resist physical and chemical practices that facilitate the non-medical use of the narcotics by various routes of administration. Such formulation technologies may impart one or more of the following abuse-deterrent characteristics to the narcotic drug product: tamper resistant secondary packaging, fabrication with crush or tear resistance laminate components, extraction resistance, formulation with prodrugs of the narcotic active ingredient, agonist and antagonist combinations, disposal systems that deactivate the residual fentanyl, and even nasal gels. For a discussion of these approaches, see U.S. Pat. No. 8,338,444 B1. While the prodrug approach modifies the drug itself, the other approaches look, at least to some extent, to formulation techniques.
Formulating or placing an opioid antagonist within the opioid agonist product is the basis of the agonist/antagonist approach to curtail misuse and abuse. If the opioid agonist product is misused or there is an attempt to extract the opioid agonist from the product, the opioid antagonist is released to decrease or even block the pharmacologic effect of the opioid agonist. U.S. Pat. Nos. 8,440,220 B2 and 8,747,889 B2 disclose an analgesic system for transdermal delivery of fentanyl and analogs thereof for analgesic purposes, to a subject through intact skin over an extended period of time. The disclosure of U.S. Pat. Nos. 8,440,220 B2 and 8,747,889 B2 are incorporated herein by reference. The transdermal analgesic system disclosed is reported to have reduced potential for abuse and a substantially minimized/negligible skin sensitization response from antagonist exposure. The transdermal analgesic system is intended to provide for the controlled release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the analgesic when the dosage form is subject to abuse. In this regard, the transdermal analgesic system is intended to provide release of the antagonist at a rate sufficient to block the opioid effects of the analgesic during abuse situations. The analgesic and antagonist layers are contained in distinct reservoir layers separated by an impermeable barrier layer. The transdermal analgesic system disclosed in U.S. Pat. Nos. 8,440,220 B2 and 8,747,889 B2, however, is not a preferred solution to potential abuse employing an antagonist reservoir and an antagonist release controlling means to modulate the ingress of water/solvent to the antagonist reservoir, to modulate the release of the antagonist during abuse while permitting the release of an antagonist at a rate to limit abuse. The transdermal analgesic system is thus complex in its formulation and in its manufacture.
In view of the existing and potential abuse and misuse of fentanyl transdermal patches there remains a need in the art to develop a fentanyl transdermal patch system which mitigates, neutralizes, or prevents the effects of fentanyl when a transdermal patch is intentionally abused or accidentally misused. This invention answers that need using a novel opioid analgesic/antagonist combination.